DESCRIPTION: The advent of next-generation sequencing (NGS) is revolutionizing biology and medicine and is rapidly becoming a standard tool for investigation. Recognizing the tremendous potential of NGS, Yale University raised the substantial capital and resources necessary to establish the Yale Center for Genome Analysis (YCGA) in 2009. YCGA has led the development of a new genome center model, focusing on a centralized facility with the highest standards of innovation, data production and analysis, but which is open access to the community rather than having projects selected by an oversight group. This scalable model has provided broad access to this technology, which has spurred innovation and eliminated barriers to experimentation by new users. By virtue of its substantial contribution to technology development for data production and analysis, accompanied by high profile scientific discoveries and success in competing for NIH funding, over the last 4 years YCGA has emerged as one of the leading genome centers in the world. YCGA produces an average of nearly 10 terabases of sequence per month, necessitating infrastructure for data storage, analysis and interpretation. YCGA's dedicated HPC instrumentation has served more than 200 users from 25 different Yale departments as well as many non-Yale investigators, and is making an enormous contribution to biomedicine ( >17 publications in Science, Nature, Cell, N Engl J Med) reporting new genes contributing to autism, cardiovascular disease, cancer, and congenital diseases of the heart and brain, as well as fundamental advances in understanding of enhancer function, mechanisms of microRNA formation, and mechanisms of evolutionary change. Part of YCGA's dedicated compute cluster and storage, is predominantly 4 years old and near the end of its productive life. This architecture must be replaced and upgraded if YCGA is to continue to serve its users. The requested HPC instrumentation will increase computational capacity to match growing demand, will greatly improving data storage and networking, and reduce the power and cooling requirements. The strengths of this proposal include; (1) an efficient and effective centralized facility serving an extremely diverse and productive investigator user base; (2) the demonstrated ability of YCGA to effectively integrate cutting edge data production and analysis for the benefit of hundreds of Yale and non-Yale researchers, (3) the extensive infrastructure and expertise that is available to bring the requested instrumentation on-line and to oversee its continuous use. Yale University has made a major investment in capital and institutional talent to build a first-rate infrastructure that ha proven highly successful. The requested instrumentation will be highly leveraged upon this existing infrastructure ensuring that it will be of high value and broad impact on NIH supported biomedical and basic research within and beyond the Yale community.